Up to 50% of infertility is due to abnormalities within the male. As the hypothalamic-pituitary-gonadal axis is central to control of human reproduction, detailed study of gonadotropin secretion in normal and infertile men is critical to understanding these disease processes. Our past studies of the regulation of gonadotropin secretion in the male have defined the role of GnRH dose, frequency, and interpulse interval as factors controlling gonadotropin secretion in GnRH deficient and normal men. In Specific Aim #1 of this proposal we will build upon this information by examining an additional variable, the strength-duration relationship (contour) of GNRH, as a potential regulator of differential gonadotropin secretion directly in the human at different windows of gonadal development, sex steroid levels and circulating inhibin concentrations. Specific Aims #2 & 3 will further investigate the regulation of gonadotropin secretion by gonadal factors, specifically as they relate to idiopathic male infertility. Specific Aim #2 will examine the role of gonadal steroids in regulating gonadotropin secretion using the combined models of castrate, Klinefelter, and oligo/azoospermic men. Specific Aim #3 will study the other major gonadal regulator of FSH secretion, inhibin, in normal men and men with various reproductive disorders. The combined goal of these 2 Specific Aims is to understand the gonadal regulation of the hormonal hallmark of idiopathic azoospermia, a differential elevation of FSH secretion which is critical to understanding the pathophysiology and in designing rational treatments for male infertility. Specific Aims #4 & 5 will use molecular techniques to define the inheritance pattern of one cause of infertility, hypogonadotropic hypogonadism. In the past we have examined the clinical and biochemical heterogeneity of this disorder. We will now use the CRI-S232 probe to examine the incidence of the X-linked pattern of inheritance of this disorder, define the spectrum of molecular and genetic defects underlying it, and screen early cases to improve fertility. By examining this particular disorder in which genetic abnormalities are likely, we will be able to design new screening techniques for hypogonadotropic hypogonadism, expand our understanding of the genetic regulation of reproduction in the human male and improve fertility potential in patients with these disorders. By studying normal men and men with reproductive disorders in tandem and by examining both the hypothalamic-pituitary and gonadal physiology and pathophysiology, we will be in position to design rational treatment for infertile men.